Process for the racemization of tetramisole

ABSTRACT

WHEREIN R1 TO R4 INCLUSIVE, EACH SEPARATELY, IS AN ALKYL GROUP HAVING 1 TO 4 CARBONS OR PHENYL AND Y IS OXYGEN OR NR5, BEING HYDROGEN OR AN ALKYL GROUP HAVING 1 TO 4 INCLUSIVE CARBONS.   Y&lt;(-C(-R1)(-R2)-C(-R3)(-R4)-)   A PROCESS OF AT LEAST PARTLY RACEMIZING AN ISOMER OF TETRAMISOLE WHICH COMPRISES HEATING SAID ISOMER TO A TEMPERATURE BETWEEN 50 AND 120* C. IN A NON-AQUEOUS, POLAR APROTIC SOLVENT MEDIUM IN THE PRESENCE OF FIRSTLY, AT LEAST ONE ONIUM SALT, SOLUBLE IN THE MEDIUM AND HAVING THE FORMULA (RNX+)Z- WHEREIN X IS N, P OR S; EACH R, SEPARATELY IS DEFINED AS AN ALKYLOR ARALKYL GROUPHAVING 1 TO 12 INCLUSIVE CARBONS, N IS 4 WHEREVER X IS N OR P AND 3 WHENEVER X IS S, AND Z IS AN ANION AS STRONGLY NUCLEOPHILIC AS, OR MORE STRONGLY NUCLEOPHILIC THAN THE BROMIDE ION AND, SECONDLY, OF AN EPOXY OR IMINO COMPOUND OF THE FORMULA:

U.S. Cl. 260306.7

United States Patent ()flice Patented Apr. 23, 1974 Int. Cl. C07d 99/109 Claims ABSTRACT OF THE DISCLOSURE A process of at least partlyracemizing an isomer of tetramisole which comprises heating said isomerto a temperature between 50 and 120 C. in a non-aqueous, polar aproticsolvent medium in. the presence of firstly, at least one onium salt,soluble in the medium and having the formula (R XHZ- wherein X is N, Por S; each R, separately is defined as an alkyl or aralkyl group having1 to 12 inclusive carbons, n is 4 whenever X is N or P and 3 whenever Xis S, and Z is an anion as strongly nucleophilic as, or more stronglynucleophilic than the bromide ion and, secondly, of an epoxy or iminocompound of the formula:

wherein R to R inclusive, each separately, is an alkyl group having 1 to4 carbons or phenyl and Y is oxygen or NR R being hydrogen or an alkylgroup having 1 to 4 inclusive carbons.

The present invention relates to the racemization of the optical isomersof tetramisole.

Tetramisole, D,L-2,3,5,6-tetrahydro 6 phenylimidazo(2,1-b)thiazole,which is subject of British Pat. No. 1,043,489, is an extremely potentanthelmintic. It is known that its anthelmintic acivity is almostentirely attributable to the optical L-isomer and in U.S. Pat. No.3,579,530 there is provided a process for the efiicient resolution ofthe racemate to the tetramisole L-isomer, which is obtained as a highlypure crystal crop.

As a by-product of this process, crude D-tetramisole is obtained whichcontains predominantly D-isomer, usually between 94 and 100%, and asmall residue of L-isomer. It will be understood by those skilled in theart that either L-isomer or D-isomer can be produced as the crystal cropin the resolution process and accordingly the byproduct in the motherliquor may be D- or L-isomer re-' spectively depending on the opticalrotation of the resolving agent used. The present process is devised toracemize D- or L-isomer; however in technical practice it is almostinvariably the biologically active L-isomer which is the desired productand D- is, therefore, the isomer to be racemized.

We have found that either optical isomer of tetramisole, particularlythe D-isomer, can be converted to the isomer of the opposite sign toyield a D,L-racemate if it is treated at elevated temperatures with amixture of a soluble onium salt of a nucleophilic anion and an epoxy oramino compound as defined below.

Accordingly we provide a process of at least partly racemizing an isomerof tetramisole which comprises heating said isomer to a temperaturebetween 50 and 120 C. in a non-aqueous, polar aprotic solvent medium inthe presence of firstly, at least one onium salt, soluble in the mediumand having the formula (R,,X+)Z- wherein X is N, P or S; each R,separately is defined as an alkyl or aralkyl group having 1 to 12inclusive carbons, n is 4 whenever X is N or P and 3 whenever X is S,and Z is an anion as strongly nucleophilic as, or more stronglynucleophilic than the bromide ion and, secondly, of an epoxy or iminocompound of the formula:

wherein R to R inclusive, each separately, is an alkyl group having 1 to4 carbons or phenyl and Y is oxygen or NR R being hydrogen or an alkylgroup having 1 to 4 inclusive carbons.

Suitable onium cations are, e.g. the alkyl ammonium or phosphoniumcations; suitable anions, with the required degree of nucleophilicityare, e.g. I, Br, SCN, the alkylsulphates and the alkane-, aralkane-,arene or alkarene sulphonate s.

Preferred onium cations are the lower alkyl ammonium ions; the preferredanion is iodide. By lower alkyl we mean an alkyl group containing from 1to 6 carbon atoms.

Particularly preferred salts are the tetra(lower alkyl) ammoniumiodides.

Suitable nucleophilic compounds of the formula:

are ethylenimine and ethylene oxide and their simple alkyl and arylhomologues. The higher epoxides and aziridines, while operative, areless convenient; the preferred reagents are, therefore, the lowesthomologue ethylenimine and ethylene oxide; most preferred isethylenimine. Suitable higher epoxides and aziridines are:2,2-dimethy1ethylenimine, l-methylethylenimine, Z-methylethylenimine,2,3-dimethylethylenimine, 2-phenylethyleniminc, propylene oxide,1,2-butylene oxide, 2,3-butylene oxide, 2,2-dimethylethylene oxide,cyclohexene oxide and styrene oxide.

Polar aprotic solvents are known, e.g. from the article by A. J. Parker(Quarterly Reviews 1962, vol. XVI, No. 2, pp. 163-187); amongst these,particularly preferred are dimethyl formamide and dimethyl sulphoxide.

Tetramisole is unstable at high temperatures. Consequently the treatmenttemperature should be as low as compatible with the required degree ofracemization; useful yields can be obtained above 50 C. and excellentyields are obtained near C. While we do not wish to be bound by theory,we consider that the reaction proceeds via a nucleophilic attack of theanion of the onium salt on the aziridine or epoxide, as shownschematically by step 1 below; the resulting anion interacts to abstracta proton from tetramisole according to step 2 below. The intermediatetetramisole anion then proceeds to abstract another proton from themedium and thus forms D- and L-isomers in equal proportions as indicatedin step 3 below; this process, over a period of time, results in partialor complete racemization.

STEP 1 A. Ethylenimine STEP 2 STEP 3 H'- D,L-tetramisole Ph y Thereagents, particularly the onium compounds, must be at least partlysoluble in the reaction medium; somewhat longer chain alkyl oniumcompounds, e.g. tetrabutyl ammonium iodide are therefore particularlysuitable.

An advantage of our invention is that the reagents are relatively cheap,common chemicals and, in contrast to other racemizing agents, e.g.lithium alkyls, are nonpyrophoric.

Our invention is now demonstrated by but not limited to the followingexamples, in which all parts unless otherwise stated are by weight.

EXAMPLE 1 D-6-phenyl-2,3,5,6-tetrahydroimidazo(2,1 b)thiazole ('a +79,C10, CHCl (10.2 g., 0.05 mol), tetrabutylammonium iodide (18.4 g., 0.05mol) and ethyleneimine (2.5 ml., 2.08 g., 0.05 mol) were dissolved in 25ml. of dry dimethylformamide. The solution was heated in a pressurebottle at 110 C. for 8 hours. After cooling, an equal volume of waterwas added. The solution was made alkaline to pH 11.5 with sodiumhydroxide and extracted with 2x 25 ml. of methylene chloride. Thecombined extracts were then extracted with 20 ml. of water, the organiclayer separated and dried over anhydrous Na SO filtered, and the solventremoved by distillation. The residual product was washed with coldn-hexane and dried. Yield 8.4 g., specific rotation a 6 (C10, CHClEXAMPLE 2 EXAMPLE 3 The procedure of Example 2 was repeated using 0.9 g.of 2,2-dimethylethylenimine instead of ethylenimine. The productobtained had a specific rotation a +6 (C10,

CHCl

EXAMPLE 4 Tetrabutylammonium iodide (18.4 g.), ethylene oxide (2.2 g.)and dry dimethylformamide (25 ml.) were heated in a pressure tube at 170C.'for hours. The mixture was cooled,'D-6-phenyl-2,3,5,6-tetrahydroimidaz0(2,1-b)thiazole (11 +79, C10, CHCl(10.2 g.) added, and heating continued at 100C. for 7 hours. Aftercooling, an equal volume of water was added. The solution was acidifiedto Congo red with dilute hydrochloric acid and extracted with 2x m1. ofmethylene chloride. The aqueous layer was made alkaline with sodiumhydroxide and extracted with 2X 25 ml. of methylene chloride. Thecombined extracts were dried over anhydrous Na SO filtered, and thesolvent removed by distillation to leave 9.6 g. of product with specificrotation a +8.6 (C10, CHCl EXAMPLE 5 The procedure of Example 4 wasrepeated using 0.6 g. of ethylene oxide and 4.6 g. of tetrabutylammoniumiodide. The product obtained had specific rotation 0: +9.2 (C10, CHCI 4EXAMPLE 6 The procedure of Example 4 was repeated using 3.6 g. of2,2-dimethylethylene oxide instead of ethylene oxide and 12.2 g. ofbutyltrimethylammonium iodide instead of tetrabutylammonium iodide. Theproduct obtained had specific rotation a +8.6 (C10, CHCl EXAMPLE 7 Theprocedure of Example 4 was repeated using 4.9 g. of cyclohexene oxideinstead of ethylene oxide and 12.9 g. tetraethylammonium iodide. Theproduct obtained had specific rotation 0: +11.2 (Cl0, CHCI EXAMPLE 8 Theprocedure of Example 4 was repeated using 16.1 g. of tetrabutylammoniumbromide instead of the iodide. The product obtained had a specificrotation e +12.7 (C10, CHCl I claim:

1. A process of at least partly racemizing an isomer of tetramisolewhich comprises heating said isomer to a temperature between 50 and 120C. in a non-aqueous, polar aprotic solvent medium in the presence offirstly, at least one onium salt, soluble in the medium and having theformula (R,,X+)Z- wherein X is N, P or S; each R, separately is definedas an alkyl or aralkyl group having 1 to 12 inclusive carbons, n is 4whenever X is N or P and 3 whenever X is S, and Z is an anion asstrongly nucleophilic as, or more strongly nucleophilic than the bromideion and, secondly, of an epoxy or imino compound of the formula:

wherein R to R inclusive, each separately, is hydrogen, an alkyl grouphaving 1 to 4 carbons or phenyl or R and R together form an alkylenegroup and wherein at least two of R to R inclusive are hydrogen atomsand wherein not more than one of R to R inclusive are phenyl groups andY is oxygen or NR R being hydrogen or an alkyl group having 1 to 4inclusive carbons.

2. A process according to claim 1 wherein R is lower alkyl and X is N.

3. A process according to claim 1 wherein Z- is I.

4. A process according to claim 1 wherein the onium salt is atetra(lower alkyl) ammonium iodide.

5. A process according to claim 1 wherein the compound of formula:

6. A process according to claim 1 wherein the compound of formula:

is ethylenimine.

7. A process according to claim 1 wherein the polar aprotic solvent isdimethyl formamide or dimethyl sulphonate.

8. A process according to claim 1 wherein the racemization is carriedout at a temperature between 50 C. and C.

9. A process according to claim 1 wherein the onium salt istetrabutylammonium iodide.

References Cited UNITED STATES PATENTS 3,673,206 6/1972 Bullock et al260-306.7

RICHARD J. GALLAGHER, Primary Examiner

